Gastro oesophageal reflux disease (GORD) is among the most common disorders seen by gastroenterologists and general practicians. The wide diversity of symptoms and disease severity produced by acid reflux has led to the need for more individualized treatment strategies. Therapeutic agents effective in the treatment of GORD include gastric acid suppressing agents, such as H.sub.2 receptor antagonists, proton pump inhibitors, other agents of interest are antacids/alginates and prokinetic agents. These agents can be distinguished by their mechanisms of action, safety profile, pharmacokinetics and indications.
Antacids and alginates are still widely used. They have a short duration of action but are seen as inexpensive and safe. They do not provide a layterm symptom resolution of GORD.
H.sub.2 receptor antagonists are widely prescribed for GORD. Their higher cost has been compensated by the clinical results obtained both in terms of symptom relief and healing. These advantages have been related to their mode of action, which offered more potent and longer duration of effect on gastric acidity.
Proton pump inhibitors, such as omeprazole, are rapidly taking share from H.sub.2 receptor antagonists, particularly in reflux oesophagitis. Omeprazole is known to offer significant gain over H.sub.2 receptor antagonists in terms of symptom resolution, healing and prevention of relapse for reflux oesophagitis.
Prokinetic agents of the first generation, e.g. bethanecol, stimulates cholinergic receptors, and of the second generation, e.g. domperidone and metoclopramide, blocks effects of endogenous dopamine in the gut. The results of double-blind placebo controlled trials in GORD patients have been conflicting. The action of the third generation of prokinetic agents, such as substituted benzamides, e.g. cisapride and mosapride derives primarily, but not exclusively, from facilitating acetylcholine release from neurones of the myenteric plexus via stimulation of 5-HT4 receptors. The efficacy of orally administered benzamides, such as cisapride, in patients with GORD and reflux oesophagitis has been studied and a superior effect in alleviating gastro-oesophageal symptoms and healing low grade oesophagitis (non circumferential erosion) has been shown in most studies.
Patients with severe symptoms, severe mucosal damage or both are almost always treated with proton pump inhibitors for profound and long-term control of gastric acid secretion. Patients with mild symptoms and limited mucosal damage respond best to H2-receptor antagonist, prokinetic agents or proton pump inhibitors.
A combination therapy of a prokinetic agent and a gastric acid lowering compound is rational and was shown more effective than mono therapy apart from full dose of proton pump inhibitors. Administration of cisapride and ranitidine was shown to further lower the exposure of the oesophagus to acid(s) (Inauen W et al. Gut 1993; 34: 1025-1031). Such a therapy was also shown to improve healing rates (de Boer WA et al. Aliment Pharmacol Ther 1994; 8: 147-157). WO 95/01803 describes a pharmaceutical composition of famitidine, cisapride and optionally simethicone in the treatment of gastrointestinal distress.
Maintenance therapy is often necessary to prevent recurrent symptoms and oesophagitis. Recently a combination therapy combining an acid-suppressing medication with a prokinetic (cisapride) was shown also very effective. Further, Vyneri et al (N. Engl. J Med 1995; 333: 1106-1110) found that omeprazole alone or in combination with cisapride was more effective than ranitidine alone or cisapride alone and that omeprazole combined with cisapride was more effective than ranitidine plus cisapride. Such combination therapies might be considered for patients whose predominant symptom is regurgitation; those whose symptoms occur mainly at night; those with respiratory problems such as posterior laryngitis, asthma, chronic bronchitis, or recurrent aspiration; those with cough and hoarseness related to reflux disease.
A combination therapy comprising an acid suppressing agent and a prokinetic agent is attractive, rational and effective. An acid suppressing agent plus a prokinetic agent could be an alternative to each of them separately in case of failure. However, because of the large number of therapeutical tablets/pills that must be taken each day in such a therapy, the compliance of such a treatment may be a problem. It is well known that patient compliance is a main factor in receiving good results in medical treatments. Administration of two, three or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results. The present invention now provides new oral dosage forms comprising two or more different active substances combined in one fixed unit dosage form, preferably a tablet.
It is well known that some of the gastric acid suppressing agents, such as proton pump inhibitors are susceptible to degradation/transformation in acid reacting and neutral media. In respect of the stability properties, it is obvious that the one of the active substances being an acid susceptible proton pump inhibitor must be protected from contact with acidic gastric juice by an enteric coating layer. There are different enteric coating layered preparations of proton pump inhibitors described in the prior art, see for example U.S. Pat No. 4,786,505 (AB Hassle) describing a preparation comprising omeprazole.
There are problems to produce a fixed unit dosage form comprising a rather high amount of active substance. Different active substances with differing physical properties in the same preparation give further problems. Preparation of a multiple unit tableted dosage form encounters specific problems when enteric coating layered pellets containing acid susceptible proton pump inhibitors as active substance are compressed into tablets. If the enteric coating layer does not withstand the compression of the pellets into a tablet the susceptible active substance will be destroyed by penetrating acidic gastric juice, i.e. the acid resistance of the enteric coating layer of the pellets will not be sufficient in the tablet after compression.